The worldwide appearance of methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), drug-resistant Streptococcus pneumnoniae, multidrug-resistant Mycobacterium tuberculosis and vancomycin-resistant enterococci (VRE) is the toughest problem in the current clinical anti-infection treatment (Exp. Opin. Ther. Patents, 2000, 10 (9): 1405; Exp. Opin. Ther. Patents, 2004, 14 (9): 1309). Facing the challenges caused by multidrug-resistant bacteria, antibacterial drugs having new action mechanisms must be developed.
Oxazolidinones are a new class of antibiotics, which has potent antibacterial activity on both multidrug-resistant gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, penicillin-resistant Streptococcus pneumoniae, and sensitive gram-positive bacteria (Angew. Chem. Int. Ed., 2003, 42: 2010; Current Topics in Medicinal Chemistry, 2003, 3: 1021). Oxazolidinones inhibit the early stage of bacterial protein synthesis. Its completely novel structure distinct from the existing antibiotics and its unique antibacterial mechanism attracted attention of numerous pharmaceutical companies. Many oxazolidinone compounds having different types of structures have been reported (Expert Opin. Ther. Patents. 2008, 18, 97-121; Anti-Infective in Medicinal Chemistry, 2008, 7, 32-49; Anti-infective in Medicinal Chemistry, 2008, 7, 258-280). Among them, linezolid developed by an American company, Upjohn, was approved by the FDA in 2000 to be firstly sold in the United States under the brand name Zyvox, thereby becoming the first oxazolidinone drug allowed to enter clinical application. However, the existing drugs have narrow antimicrobial spectrum, unsatisfied antibacterial activity and side effects such as bone marrow suppression, and furthermore, linezolid-resistant staphylococci and enterococci have appeared in clinics. Therefore, there is a need for researching and developing new oxazolidinone drugs with stronger antibacterial activity, lower side effects, and particularly, with effectiveness on linezolid-resistant strains.
The present invention provides a class of novel oxazolidinone compounds with stronger antibacterial activities, particularly activities against multidrug-resistant bacteria.